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Screening a Natural Product-Based Library Against Kinetoplastid Parasites

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Screening a Natural Product-Based Library Against Kinetoplastid Parasites molecules Article Screening a Natural Product-Based Library against Kinetoplastid Parasites Bilal Zulfiqar 1, Amy J. Jones 1, Melissa L. Sykes 1, Todd B. Shelper 1, Rohan A. Davis 2 ID and Vicky M. Avery 1,* 1 Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia; bilal.zulfiqar@griffithuni.edu.au (B.Z.); a.jones@griffith.edu.au (A.J.J.); m.sykes@griffith.edu.au (M.L.S.); t.shelper@griffith.edu.au (T.B.S.) 2 Natural Product Chemistry, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia; r.davis@griffith.edu.au * Correspondence: v.avery@griffith.edu.au; Tel.: +61-(0)737-356-056 Received: 5 September 2017; Accepted: 4 October 2017; Published: 12 October 2017 Abstract: Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world’s lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the need to identify new treatments. In this study, the Davis open access natural product-based library was screened against kinetoplastids (Leishmania donovani DD8, Trypanosoma brucei brucei and Trypanosoma cruzi) using phenotypic assays. The aim of this study was to identify hit compounds, with a focus on improved efficacy, selectivity and potential to target several kinetoplastid parasites. The IC50 values of the natural products were obtained for L. donovani DD8, T. b. brucei and T. cruzi in addition to cytotoxicity against the mammalian cell lines, HEK-293, 3T3 and THP-1 cell lines were determined to ascertain parasite selectivity. Thirty-one compounds were identified with IC50 values of ≤10 µM against the kinetoplastid parasites tested. Lissoclinotoxin E (1) was the only compound identified with activity across all three investigated parasites, exhibiting IC50 values <5 µM. In this study, natural products with the potential to be new chemical starting points for drug discovery efforts for kinetoplastid diseases were identified. Keywords: natural products; kinetoplastids; neglected tropical disease; drug discovery; leishmaniasis; human African trypanosomiasis; Chagas disease 1. Introduction Trypanosomatida is a group of kinetoplastid protozoa differentiated into the genus Leishmania and Trypanosoma. Parasites belonging to the genus Leishmania are the causative agents of leishmaniasis, while Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense are the causative agents of human African trypanosomiasis (HAT). The other parasite in the genus Trypanosoma is Trypanosoma cruzi, which is responsible for Chagas disease. Around 20 million individuals are infected with kinetoplastid pathogens worldwide leading to 95,000 deaths per year [1]. For Chagas disease and HAT the primary areas of transmission are Latin America and sub-Saharan Africa, respectively [2]. Leishmaniasis is endemic to 98 countries around the globe [3]. The vector for leishmaniasis is the Phlebotomus sand-fly in the Old World and the Lutzomyia sand-fly in the New World [4]; while T. b. gambiense and T. b. rhodesiense are transmitted by the bite of a tsetse fly [5]. T. cruzi is primarily transmitted by triatomine bugs to humans through contact with bug faeces or urine at the site of a bite [6]. Molecules 2017, 22, 1715; doi:10.3390/molecules22101715 www.mdpi.com/journal/molecules Molecules 2017, 22, 1715 2 of 19 The complex multiple host life cycles of these kinetoplastids provides a challenge for drug discovery efforts thus it is preferable that where possible, drugs are able to target several of these life cycle stages, species and in addition, stages of infection. The life cycle of the Leishmania parasite constitutes two key forms; the promastigotes which reside within the gut of the sand fly and the intracellular amastigotes within the mammalian host macrophages [7]. Based on clinical manifestations, leishmaniasis can be differentiated into cutaneous, mucocutaneous and visceral leishmaniasis [8]. T. b. gambiense and T. b. rhodesiense exist as extracellular forms in the tsetse fly as procyclic and metacyclic trypomastigotes. Once injected into the host, they transform into bloodstream trypomastigotes. HAT progresses in two stages: a hemolymphatic stage and a central nervous system (CNS) stage [9]. The T. cruzi life cycle involves three distinct stages; epimastigotes reside within the gut of the triatomine bug where they divide and differentiate into infective metacyclic trypomastigotes in the hindgut. Like leishmaniasis, inside the host they transform into intracellular amastigotes within the infected cell. In Chagas disease; early (acute) stage of the disease may be asymptomatic or display only mild symptoms, while a latter, chronic stage results in cardiac disorders (30%) or digestive disorders (10%), due to the parasite residing in the tissue, or due to associated inflammation in tissue free of the parasite [10]. Kinetoplastid diseases are extremely debilitating and can be fatal without treatment [11]. Existing treatments for leishmaniasis such as miltefosine and amphotericin B deoxycholate [12] have limitations and toxicities associated with them. Current treatments for HAT including pentamidine and eflornithine have variable efficacy at the different stages of the disease and against the different subspecies of T. brucei, and are fraught with severe side effects [13]. For Chagas disease, treatment with the drugs benznidazole and nifurtimox is most effective in the early stages of the disease, but efficacy diminishes with duration of infection [14]. Collectively, the therapies available for kinetoplastid diseases are inadequate, lack efficacy and possess extensive toxicity. Additionally, there is evidence of emerging or potential resistance in leishmaniasis [15], HAT [16], Chagas disease [17] and access to the drugs in remote areas is limited [18–20]. Despite the new drug leads currently in clinical trials for leishmaniasis [21–23], HAT [24–26] and Chagas disease [27], there exists a high attrition rate [28,29] and new molecules with novel mechanisms of action are required. Natural products have traditionally been used to treat parasitic diseases, primarily through ethnopharmacology approaches [30]. More recent efforts to elucidate the structural and biological properties of the chemical entities within complex anti-parasitic natural product extracts have identified molecules with significant potential for treating NTD’s. For example, recently the antiprotozoal activity of the isolated alkamide dodeca-2E,4E-dienoic acid 4-hydroxy-2-phenyl-ethylamide from Anacyclus pyrethrum roots has been reported against L. donovani, T. b. rhodesiense, T. cruzi and the NF54 strain of Plasmodium falciparum with an IC50 of 4.19 ± 1.64, 2.26 ± 0.18, 1.88 and 3.18 ± 0.20 µM, respectively [31]. Australia has a high level of biodiversity providing an exceptional resource for natural product drug discovery. We have previously reported the identification and biological profiling of compounds originating from plants [32], marine invertebrates [33–35] and fungi [36], which possess anti-parasitic activity. In our continuing search for new anti-parasitic compounds from nature, we report here the identification of several bioactive molecules with activity across multiple life cycle stages of three kinetoplastids, L. donovani DD8 (visceral leishmaniasis: intracellular amastigotes and extracellular promastigotes residing in the gut of sandfly), T. b. brucei (a surrogate species for HAT: bloodstream trypomastigotes) and T. cruzi (Chagas disease: intracellular amastigotes). This is the first evaluation of the unique Davis open access natural product-based library against kinetoplastids which has resulted in the identification of several compounds with novel anti-kinetoplastid activities. Molecules 2017, 22, 1715 3 of 19 2. Results 2.1. Screening Campaigns and Hit Identification 2.1.1. L. donovani DD8 Promastigote and Intracellular Amastigote Screening Twenty nine compounds exhibited >70% activity at 16.7 µM against promastigotes with a hit rate of 6.14%. Twelve compounds were active against intracellular amastigotes, with ≥70% inhibition at 20 µM. Of these, 6 compounds showed cytotoxicity against THP-1 cells at 20 µM. Following retest, five compounds exhibited IC50 values of <10 µM against L. donovani DD8 intracellular amastigotes. These five compounds demonstrated comparable activity against both forms (namely promastigote and amastigote), whereas compound (1) (Figure1) exhibited more potent activity against the promastigotes (IC50: 0.73 ± 0.16 µM) than the amastigotes (IC50: 4.41 ± 0.24 µM). Of these compounds, compound (13) displayed good selectivity of ~12 against the parasite in relation to HEK-293 cells. The Z’ of the intracellular amastigote and promastigote viability assays for primary screen and retest indicated high reproducibility with values of (0.75, 0.72) and (0.91, 0.90), respectively. A Z’ for assays using THP-1 and HEK-293 cells were calculated to be (0.70, 0.69) and (0.78, 0.72), respectively. The IC50 values for the reference drugs amphotericin B and miltefosine were 0.12 ± 0.01 µM, 0.20 ± 0.02 µM and 3.48 ± 0.26 µM, 2.54 ± 0.57 µM for the promastigote viability and intracellular amastigote assays, respectively (Table1). The IC 50 value for miltefosine was 2.54 ± 0.57 µM in the amastigote assay, which is consistent with data previously reported in the literature (3.1 ± 2.3 µM) [37]. 2.1.2.
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